DESCRIPTION (adapted from the application) Normal water metabolism is essential to body fluid homeostasis. The major determinants of normal water balance include arginine vasopressin (AVP), renal function, and thirst. Recent investigations have described the cloning and characterization of the water channel aquaporin-2 (AQP-2), which is located in the principal cell of the kidney collecting duct. Under the influence of AVP, AQP-2 inserts into the apical membrane, allowing reabsorption of water to occur. Studies in animals and humans suggest that alterations in the regulation and expression of AQP-2 in certain physiologic and pathologic states may contribute to such complications as hyponatremia, hypoosmolality, and edema. During exocytic shuttling of AQP-2 to the apical collecting duct membrane, a small percentage of AQP-2 is lost in the urine. Measurement of this urinary AQP-2 protein can be reliably performed by radioimmunoassay; this test represents a novel tool for evaluation of AVP action in the collecting duct of the human kidney in health and disease. In these studies, we will examine urinary AQP-2 excretion in patients during pregnancy and the menstrual cycle, and in patients with congestive heart failure, cirrhosis, nephrotic syndrome, and acquired nephrogenic diabetes insipidus due to lithium therapy or autosomal dominant polycystic kidney disease. An interpretation of the relationship between urinary AQP-2, serum and urine osmolality, and plasma AVP will provide insight into the control of body fluid homeostasis. The role of the vasopressin V2 receptor antagonist, CIPC-41061, in the treatment of volume overload, edema, and hyponatremia will be explored. A comprehensive understanding of AQP-2 regulation in humans will lead to unique and more direct interventions in the therapy of disordered water metabolism.